The present invention relates to therapeutically active azabicyclic compounds, a method of preparing the same and to pharmaceutical or veterinary compositions comprising the compounds. The novel compounds are useful in treating a disease in the central nervous system caused by malfunctioning of the muscarinic cholinergic system.
Due to the generally improved health situation in the western world, elderly-related diseases are much more common now than in the past and are likely to be even more common in the future.
One of the elderly-related symptoms is a reduction of the cognitive functions. This symptom is especially pronounced in the pathophysiological disease known as Alzheimer""s disease. This disease is combined with, and also most likely caused by, an up to 90% degeneration of the cholinergic neurons in nucleus basalis, which is part of substantia innominata. These neurons project to the pre-frontal cortex and hippocampus and have a general stimulatory effect on the cognitive functions of the forebrain as well as of hippocampus, namely learning, association, consolidation, and recognition.
It is a characteristic of Alzheimer""s disease that although the cholinergic neurons degenerate, the postsynaptic muscarinic receptors in the forebrain and hippocampus still exist. Therefore, muscarinic cholinergic agonists are useful in the treatment of Alzheimer""s disease, in halting progression of Alzheimer""s disease, and in improving the cognitive functions of elderly people.
The compounds of this invention are also useful analgesic agents and therefore useful in the treatment of severe painful conditions.
Furthermore, the compounds of this invention are useful in the treatment of glaucoma, psychosis, mania, bipolar disorder, schizophrenia or schizophreniform conditions, depression, bladder dysfunctions, anxiety, sleeping disorders, epilepsy, cerebral ischemia and gastrointestinal motility disorders.
It is an object of the invention to provide new muscarinic cholinergic compounds.
The novel compounds of the invention are heterocyclic compounds having formula I 
wherein W is oxygen or sulphur; R is selected from the group consisting of hydrogen, amino, halogen, NHR6, NR6R7, R4, xe2x80x94OR4, xe2x80x94SR4, xe2x80x94SOR4, xe2x80x94SO2R4, C3-10-cycloalkyl, C4-12-(cycloalkylalkyl), xe2x80x94Zxe2x80x94C3-10-cycloalkyl and xe2x80x94Zxe2x80x94C4-12-(cycloalkylalkyl) which is optionally substituted with C1-6-alkyl; R4 is selected from the group consisting of C1-15-alkyl, C2-15-alkenyl, C2-15-alkynyl and C4-15-alkenynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), xe2x80x94CF3, xe2x80x94CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of xe2x80x94OH, halogen, xe2x80x94NO2, xe2x80x94CN, C1-4-alkyl, C1-4-alkylthio, C1-4-alkoxy, xe2x80x94SCF3, xe2x80x94OCF3, xe2x80x94CF3, xe2x80x94CONH2 and xe2x80x94CSNH2; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen, xe2x80x94CN, C1-4-alkyl, C1-4-alkoxy, xe2x80x94OCF3, xe2x80x94CF3, xe2x80x94CONH2 and xe2x80x94CSNH2; or R is selected from the group consisting of xe2x80x94OR5Y, xe2x80x94SR5Y, OR5ZY, xe2x80x94SR5ZY, xe2x80x94OR5ZR4 and xe2x80x94SR5ZR4; Z is oxygen or sulphur; R5 is C1-15-alkylene, C2-15-alkenylene, C2-15-alkynylene or C4-15-alkenynylene; Y is a 5 or 6 membered heterocyclic group optionally substituted with one or more independently selected from the group consisting of xe2x80x94OH, halogen, xe2x80x94NO2, xe2x80x94CN, C1-14-alkyl, C1-4-alkylthio, C1-4-alkoxy, xe2x80x94SCF3, xe2x80x94OCF3, xe2x80x94CF3, xe2x80x94CONH2 and xe2x80x94CSNH2; G is 
R6 and R7 independently are selected from the group consisting of hydrogen and C1-6-alkyl; or R6 and R7 together with the nitrogen atom optionally form a 4- to 6-membered ring; R1 and R2 independently are selected from the group consisting of hydrogen, xe2x80x94OH, xe2x95x90O, C1-15-alkyl, C2-15-alkenyl, C2-15-alkynyl, C1-10-alkoxy, and C1-5-alkyl substituted with one or more independently selected from the group consisting of xe2x80x94OH, xe2x80x94COR8, xe2x80x94CH2OH, halogen, xe2x80x94NH2, carboxy and phenyl; R8 is hydrogen, C1-8-alkyl; r is 0, 1 or 2; xc2x7 xc2x7 xc2x7 is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.
As used herein, the term xe2x80x9chalogenxe2x80x9d means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and F.
The terms xe2x80x9cC1-nxe2x80x2-alkylxe2x80x9d wherein nxe2x80x2 can be from 2 through 15, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms. Typical C1-6-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
The terms xe2x80x9cC2-nxe2x80x2-alkenylxe2x80x9d wherein nxe2x80x2 can be from 3 through 15, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like.
The terms xe2x80x9cC2-nxe2x80x2-alkynylxe2x80x9d wherein nxe2x80x2 can be from 3 through 15, as used herein, represent an unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.
The terms xe2x80x9cC4-nxe2x80x2-alkenynylxe2x80x9d wherein nxe2x80x2 can be from 5 through 15, as used herein, represent an unsaturated branched or linear hydrocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1-penten-4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and the like.
The term xe2x80x9cC3-n-cycloalkylxe2x80x9d wherein n=4-10, as used herein, represents e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like.
As used herein the term C4-12-(cycloalkylalkyl) represents a branched or linear alkyl group substituted at a terminal carbon with a cycloalkyl group. Typical cycloalkylalkyl groups include cyclopropylethyl, cyclobutylmethyl, cyclohexylethyl, cyclohexylmethyl, 3-cyclopentylpropyl, and the like.
As used herein, the term xe2x80x9cC1-4-alkoxyxe2x80x9d represents methoxy, ethoxy, propoxy, butoxy and the like.
As used herein, the phrase xe2x80x9cone or more selected fromxe2x80x9d shall more preferably refer to from 1-3 substituents. The term shall further preferably refer to from 1-2 substituents.
As used herein, the phrase xe2x80x9c5 or 6 membered heterocyclic groupxe2x80x9d means a group containing from one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with xe2x80x94OH, halogen, xe2x80x94NO2, xe2x80x94CN, C1-4-alkyl, C1-4-alkylthio, C1-4-alkoxy, xe2x80x94SCF3, xe2x80x94OCF3, xe2x80x94CF3, xe2x80x94CONH2 and xe2x80x94CSNH2, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group. The phrase xe2x80x9c5 or 6 membered heterocyclic groupxe2x80x9d includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes, pyrroles, furans); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heterocycles having three heteroatoms (e.g. triazoles, thiadiazoles); 5-membered heterocycles having four heteroatoms; 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthridine, cyclohepta[b]pyridine); 6-membered heterocycles with two heteroatoms (e.g. pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heterocycles with three heteroatoms (e.g. 1,3,5-triazine); and 6-membered heterocycles with four heteroatoms.
As used herein with reference to the G substituent, the xe2x80x94(CH2)r-W-thiadiazole moity can be attached at any carbon atom of the azabicyclic ring. Further, R1 and R2 of the G substituent may be present at any position, including the point of attachment of the xe2x80x94(CH2)r-W-thiadiazole moity.
As used herein the phrase xe2x80x9cR6 and R7 together with the nitrogen atom optionally form a 4- to 6-member ringxe2x80x9d means that R6 and R7 are each independently hydrogen, C1-5-alkyl wherein the R8 and R7 groups may optionally join to form a 4- to 6-member ring including the nitrogen. For example, optionally joined groups include, but are not limited to: 
As used herein the term xe2x80x9ccarboxyxe2x80x9d refers to a substituent having the common meaning understood by the skilled artisan, wherein the point of attachment may be through the carbon or oxygen atom of the group.
As used herein, the term xe2x80x9calkoxide metalxe2x80x9d means a metal suitable for alkoxide formation. Such alkoxide metals include, but are not limited to, Li+, K+, Na+, Cs+, and Ca++. Especially preferred alkoxide metals include Li+, K+, and Na+.
In a preferred embodiment, the present invention is concerned with compounds of formula I wherein G is saturated.
In another preferred embodiment, the present invention is concerned with compounds of formula I wherein G is 
and wherein the xe2x80x94(CH2)rxe2x80x94W-thiadiazole is attached to the 3- or 4-position of G.
In another preferred embodiment, the present invention is concerned with compounds of formula I wherein G is 
In another preferred embodiment, the present invention is concerned with compounds of formula I wherein r is 0.
In another preferred embodiment, the present invention is concerned with compounds of formula I wherein W is oxygen.
In another preferred embodiment, the present invention is concerned with compounds of formula I wherein R is xe2x80x94OR4, xe2x80x94SR4, xe2x80x94SOR4, xe2x80x94SO2R4, xe2x80x94Zxe2x80x94C3-10-cycloalkyl or xe2x80x94Zxe2x80x94C4-12-(cycloalkylalkyl) which is optionally substituted with C1-6-alkyl or R is xe2x80x94OR5Y, xe2x80x94SR5Y, xe2x80x94OR5ZY, xe2x80x94SR5ZY, xe2x80x94OR5ZR4 or xe2x80x94SR5ZR4, preferably R is xe2x80x94OR4, xe2x80x94SR4, xe2x80x94OR5ZY, xe2x80x94SR5ZY, xe2x80x94OR5ZR4 or xe2x80x94SR5ZR4.
In another preferred embodiment, the present invention is concerned with compounds of formula I wherein R4 is C1-15-alkyl, C2-15-alkenyl, C2-15-alkynyl or C4-15-alkenynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), xe2x80x94CF3, xe2x80x94CN, Y and phenyl which is optionally substituted with one or more independently selected from the group consisting of xe2x80x94OH, halogen, xe2x80x94CN, C1-4-alkyl, C1-14-alkylthio, C1-4-alkoxy, xe2x80x94SCF3, xe2x80x94OCF3, and CF3.
In another preferred embodiment, the present invention is concerned with compounds of formula I wherein R is xe2x80x94OR4 or xe2x80x94SR4, wherein R4 is straight or branched C2-8-alkynyl, preferably propynyl, substituted with phenyl or Y, preferably Y is thiophene, pyridine, furan or thiazole, each of which is optionally substituted with xe2x80x94OH, halogen, xe2x80x94NO2, xe2x80x94CN, C1-4-alkyl, C1-4-alkylthio, C1-4-alkoxy, xe2x80x94SCF3, xe2x80x94OCF3, xe2x80x94CF3, xe2x80x94CONH2 or xe2x80x94CSNH2, preferably halogen, xe2x80x94CN, C1-4-alkoxy or xe2x80x94OCF3.
It is to be understood that the invention extends to each of any of the stereoisomeric forms of the compounds of the present invention as well as the pure diastereomeric, pure enantiomeric, and racemic forms of the compounds of this invention.
The starting materials for the illustrated process are, if nothing else mentioned, commercially available or may be prepared using methods known to the skilled artisan.
The invention also relates to methods of preparing the above mentioned compounds, comprising
a) reacting a compound of formula II
NCxe2x80x94CNxe2x80x83xe2x80x83(II)
xe2x80x83with first HSR4/Et2NH and subsequently S2Hal2, wherein R4 has the meaning defined above, to form a compound of formula III 
xe2x80x83wherein R has the meaning defined above; or the compound of formula II is first reacted with HOR4/Et3N and subsequently with S2Hal2, wherein R4 has the meaning defined above, to form a compound of formula IV 
xe2x80x83wherein R4 has the meaning defined above; and a compound of formula III or formula IV can subsequently be reacted in the presence of an alkoxide metal with a compound of formula V
Gxe2x80x94(CH2)r xe2x80x94Wxe2x80x94Hxe2x80x83xe2x80x83(V)
xe2x80x83wherein G, r and W have the meanings defined above, to form a compound of formula VI selected from the following 
xe2x80x83wherein G, R, W and R4 have the meanings defined above; or
b) a compound of formula III can be oxidized to form a compound of formula VII 
xe2x80x83wherein R4 has the meaning defined above, which subsequently can be reacted with a compound of formula V to form a compound of formula VIII 
xe2x80x83wherein G, r and W have the meanings defined above which compound can subsequently be reacted with either Rxe2x80x94OH or RMgHal to form a compound of formula I; or
c) a compound of formula VI 
xe2x80x83wherein G, r, W and R4 have the meanings defined above, can be oxidized to form a compound of formula IX 
xe2x80x83wherein G, r, W and R4 have the meanings defined above which compound subsequently can be reacted with either Rxe2x80x94OH or RMgHal to form a compound of formula I.
The term xe2x80x9cHalxe2x80x9d refers to Cl or Br. Preferred oxidizing agents for the process include oxone and sodiumperiodate. Oxone is an especially preferred oxidizing agent.
As is always the case in chemistry, the rate of the reaction depends on a variety of factors, such as the temperature and the exact compound which is to be prepared. The course of the reaction may be followed using methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC) and nuclear magnetic resonance spectroscopy (NMR) to detect the degree of completion of the reaction. The operator may obtain maximum yields using the process by extending the reaction time. Alternatively, the operator may wish to obtain maximum throughput by cutting off the reaction at the point at which it reaches an economical degree of completion.
When the product of a step in the following process is an oil, it may be isolated by standard methods. Such methods include distillation, flash chromatography, HPLC and the like.
The invention further provides a formulation comprising a compound of formula I and one or more pharmaceutically acceptable diluents, carriers or excipients therefor.
The invention provides a method for treating a condition associated with a malfunction of the cholinergic muscarinic receptor system. Such conditions which may be treated using a compound of this invention include, but are not limited to
Alzheimer""s Disease, cognitive dysfunction, severely painful conditions, glaucoma, psychosis, schizophrenia, bladder dysfunction, anxiety, sleep disorders, and other such conditions associated with the modulation of a muscarinic receptor.
As used herein the term xe2x80x9ctreatingxe2x80x9d includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been estabished or alleviation of the characteristic symptoms of such condition.
As used herein the term xe2x80x9cmalfunctioning of the muscarinic cholinergic systemxe2x80x9d shall have the meaning accepted by the skilled artisan. For example the term shall refer to, but is not in any way limited to conditions such as glaucoma, psychosis, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy and gastrointestinal motility disorders. Other such conditions include Alzheimer""s disease and incontinence.
As used herein the phrase xe2x80x9cinteracting with a muscarinic cholinergic receptorxe2x80x9d shall include compounds which block muscarinic cholinergic receptors or modulate such receptors. The phrase shall include the effect observed when compounds act as agonists, partial agonists and/or antagonists at a muscarinic cholinergic receptor.
Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
The pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of 3H-Oxotremorine-M (3H-Oxo). Birdsdall N. J. M., Hulme E. C., and Burgen A. S. V. (1980). xe2x80x9cThe Character of Muscarinic Receptors in Different Regions of the Rat Brainxe2x80x9d. Proc. Roy. Soc. London (Series B) 207, 1.
3H-Oxo labels muscarinic receptor in the CNS (with a preference for agonist domains of the receptors). Three different sites are labelled by 3H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.
The inhibitory effects of compounds on 3H-Oxo binding reflects the affinity for muscarinic acetylcholine receptors.
All preparations are performed at 0-4xc2x0 C. unless otherwise indicated. Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenized for 5-10 s in 10 ml 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 10 ml of buffer and the combined suspension centrifuged for 15 min. at 40,000xc3x97g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2xc3x9710 ml of buffer and centrifuged for 10 min. at 40,000xc3x97g.
The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 ml per g of original tissue) and used for binding assay. Aliquots of 0.5 ml is added 25 xcexcl of test solution and 25 xcexcl of 3H-Oxotremorine (1.0 nM, final concentration) mixed and incubated for 30 min. at 25xc2x0 C. Non-specific binding is determined in triplicate using arecoline (1 xcexcg/ml, final concentration) as the test substance. After incubation samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 ml of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.
Test substances are dissolved in 10 ml water (if necessary heated on a steambath for less than 5 min.) at a concentration of 2.2 mg/ml. 25-75% inhibition of specific binding must be obtained before calculation of IC50.
The test value will be given as IC50 (the concentration (nM) of the test substance which inhibits the specific binding of 3H-Oxo by 50%).
IC50=(applied test substance concentration)xc3x97(Cx/Coxe2x88x92Cx)nM
where Co is specific binding in control assays and Cx is the specific binding in the test assay. (The calculations assume normal mass-action kinetics).
Furthermore the pharmacological properties of the compounds of the invention can also be illustrated by determining their capability to inhibit 3H-PRZ (pirenzepine, [N-methyl-3H]) binding to rat cerebral cortex membranes. Pirenzepine binds selectively to subtype of muscarinic receptors. Historically the type is named the M1-site, whereas pirenzepine sensitive site would be more appropriate. Although selective for M1-sites pirenzepine also interact with M2-sites.
All preparations are performed at 0-4xc2x0 C. unless otherwise indicated. Fresh cortex (0.1-1 g) from male Wistar rats (150-200 g) is homogenized for 5-10 s. in 10 ml 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 2xc3x9710 ml of buffer and the combined suspension centrifuged for 15 min at 40,000xc3x97g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 3xc3x9710 ml of buffer and centrifuged for 10 min at 40,000xc3x97g.
The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 ml per g of original tissue) and used for binding assay. Aliquots of 0.5 ml is added 20 xcexcl of test solution and 25 xcexcl of 3H-Pirenzepine (1.0 nM, final conc.), mixed and incubated for 60 min at 20xc2x0 C. Non-specific binding is determined in triplicate using atropine (1 xcexcg/ml, final conc.) as the test substance. After incubation samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 ml of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.
Test substances are dissolved in 10 ml water, at a concentration of 0.22 mg/ml. 25-75% inhibition of specific binding must be obtained before calculation of IC50.
The test value will be given as IC50 (the concentration (nM) of the test substance which inhibits the specific binding of 3H-PRZ by 50%).
IC50=(applied test substance concentration)xc3x97(Cx/Coxe2x88x92Cx)nM
where Co is specific binding in control assays and Cx is the specific binding in the test assay. (The calculations assume normal mass-action kinetics).
Test results obtained by testing some compounds of the present invention will appear from the following table 1:
By testing the compounds of the present invention it is found that they inhibit the specific binding of 3H-Oxotremorine-M and 3H-Pirenzepine.
The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 0.1 mg to about 70 mg per day. In choosing a regimen for patients suffering from diseases in the central nervous system caused by malfunctioning of the muscarinic cholinergic system it may frequently be necessary to begin with a dosage of from about 20 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 0.1 to about 10 mg per day. The exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by empolying procedures well known in the art.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
Generally, the compounds are dispensed in unit form comprising from about 0.1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
The compounds according to this invention may be suitable for administration to an animal. Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferably, the animal is a vertebrate. Most preferably, a compound according to this invention shall be administered to a mammal. It is especially preferred that the animal is a domestic mammal or a human. The most preferred mammal is a human. For such purposes, a compound of this invention may be administered as a feed additive or in bulk form.
The invention will now be described in further detail with reference to the following examples. The examples are provided for illustrative purposes, and are not to be construed as limiting the scope of the invention in any way.